Pulses to Brain Work Long-Term in Refractory Seizure Control

by John Gever John Gever Senior Editor, MedPage Today
December 03, 2012

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This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

This report describes long-term follow-up of bilateral stimulation of the anterior nuclei of the thalamus in patients with refractory partial onset seizure epilepsy and shows sustained efficacy and continuous improvement over 5 years.

SAN DIEGO -- Responses to deep brain stimulation (DBS) in patients with severely refractory partial onset seizure epilepsy continued to increase over 5 years of follow-up in the SANTE trial, researchers said here.

Reductions of at least 50% in seizure frequency were eventually seen in 69% of patients in the study, with the median reduction in seizure frequency also standing at 69%, said Vicenta Salanova, MD, of Indiana University in Indianapolis.

Speaking at the American Epilepsy Society's annual meeting, Salanova said that 16% of the patients remained seizure free for periods of at least 6 months.

Her presentation was a follow-up to 2-year results published in 2010, which had shown a responder rate (at least 50% reduction in seizure frequency) of 54%.

The SANTE (Stimulation of the Anterior Nuclei of Thalamus for Epilepsy) trial initially enrolled 110 patients who were averaging at least six partial or secondarily generalized seizures per month despite treatment with at least three different anti-epileptic drugs. Some patients also failed surgical therapies, Salanova said.

Akin to DBS for Parkinson's disease, and using the same type of device, the intervention involved implantation of the pulse generator in the upper torso with leads into the thalamus.

A total of 102 patients stayed in the trial for 2 years, and 83 completed 5 years of follow-up.

The trial was conceived and funded by Medtronic as a pivotal study aimed at winning approval for its DBS system as a treatment for drug-refractory epilepsy marked by frequent partial onset seizures.

However, it has failed for that goal, at least in the U.S., as the FDA has thus far declined to approve the indication (although it is now approved in Canada and Europe). That apparently was because SANTE did not show a significant benefit for DBS over the study's initial 3-month randomized, blinded phase during which some patients received the pacemaker-like device but switched off.

Medtronic had argued that the apparent lack of benefit during the randomized phase was due to a single "outlier" patient in the active DBS group. That patient had shown an enormous flurry of seizures -- 210 in the first 3 days after the device was turned on -- that largely abated when the device settings were changed.

He subsequently appeared before the FDA advisory committee that met to review the system's epilepsy indication to lobby for a positive recommendation. The panel did support approval, but by a narrow 7-5 vote that the FDA apparently did not consider a real endorsement.

Panel members at the time cited the ambiguous evidence of efficacy as well as some worrisome safety signals, including depression and suicidal ideation as well as three cases of definite or possible SUDEP (sudden unexplained death in epilepsy) among patients receiving active therapy, according to the FDA's analysis.

But Salanova suggested that the 5-year data should dispel those concerns.

After the 3-month sham-controlled phase, patients in the control group had their devices switched on and were followed along with the initial active-treatment group.

No additional SUDEP cases occurred during the last 3 years of follow-up. Salanova and colleagues calculated that the risk of SUDEP among trial participants was 3.2 per 1,000 patient-years, although they did not count the one possible SUDEP case, as their prespecified protocol called for only "definite or probable" cases to be included.

But even with the possible SUDEP case included, the rate would be less than the 9.3 per 1,000 patient-years, considered to be the standard risk in drug-refractory epilepsy patients.

The primary 5-year efficacy outcomes were calculated on the basis of the 59-patient subset who maintained seizure diaries for at least 70 days. In those patients, the median reduction in seizure frequency was 69%.

When the results were compiled on a more stringent intention-to-treat basis, the benefit was not so great, but still substantial, Salanova's group indicated.

With study dropouts assumed to have returned to their baseline seizure frequencies, the median reduction in seizure frequency after 5 years was 51%, and exactly half of patients were classed as responders at the 50% reduction level.

Median reductions in seizure frequency and responder rates remained the same or increased with lengthening follow-up even in the most stringent analyses.

Secondary endpoints including scores on the Liverpool Seizure Severity Scale and the Quality of Life in Epilepsy index. Both showed substantial improvements from baseline that appeared to grow with longer follow-up.

At year 5, the mean Liverpool score had declined 18.5 points from baseline (P<0.001). Mean quality of life score had increased 6.2 points from baseline (P<0.001).

Nonfatal adverse events were led by depression (27%), followed by memory impairment (18%), status epilepticus (3%), and suicidality (9%).

Paul A.J.M. Boon, MD, PhD, of the University of Ghent in Belgium, commented that electrical stimulation therapies such as DBS could become an attractive alternative to surgical ablation procedures.

"Resective surgery, which is still the gold standard therapy for some of these difficult cases, is a very good therapy, there's no question about it," he said, but added that "loss of neuropsychological functioning and cognitive loss" are very common following surgery.

Other physicians told MedPage Today that such concerns frequently turn drug-refractory patients away from surgery, raising their risk of SUDEP and the other negative consequences of poorly controlled seizure activity.

"The hope would be that, if we succeed in optimizing the deep brain stimulation therapies, it would limit or strictly stop seizures without affecting cognitive function," Boon said.

The study was funded by Medtronic.

Other than the funding from Medtronic, Salanova reported no potential conflicts of interest. Boon indicated he had no relevant financial interests, but he is currently leading a trial of another type of brain stimulation therapy.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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